Synthesis and discovery of a drug candidate for treatment of idiopathic pulmonary fibrosis through inhibition of TGF-β1 pathway

Xiaohe Li; Cheng Lu; Shuangwei Liu; Shuaishuai Liu; Chengcheng Su; Ting Xiao; Zhun Bi; Pengzhen Sheng; Mengying Huang; Xinhua Liu; Yujiao Wei; Lin Zhao; Shengxiang Miao; Jiahe Mao; Kai Huang; Shaoyan Gao; Ning Liu; Min Qi; Tongtong Liu; Shuanglin Qin; Luqing Wei; Tao Sun; Wen Ning; Guang Yang; Honggang Zhou; Cheng Yang

doi:10.1016/j.ejmech.2018.07.074

Synthesis and discovery of a drug candidate for treatment of idiopathic pulmonary fibrosis through inhibition of TGF-β1 pathway

Eur J Med Chem. 2018 Sep 5:157:229-247. doi: 10.1016/j.ejmech.2018.07.074. Epub 2018 Aug 3.

Authors

Xiaohe Li¹, Cheng Lu¹, Shuangwei Liu¹, Shuaishuai Liu¹, Chengcheng Su², Ting Xiao¹, Zhun Bi¹, Pengzhen Sheng¹, Mengying Huang¹, Xinhua Liu¹, Yujiao Wei¹, Lin Zhao¹, Shengxiang Miao¹, Jiahe Mao¹, Kai Huang¹, Shaoyan Gao¹, Ning Liu¹, Min Qi¹, Tongtong Liu¹, Shuanglin Qin¹, Luqing Wei², Tao Sun¹, Wen Ning¹, Guang Yang³, Honggang Zhou⁴, Cheng Yang⁵

Affiliations

¹ College of Pharmacy, The State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, People's Republic of China.
² Department of Respiratory and Critical Care Medicine, Pingjin Hospital, Logistics University of Chinese People's Armed Police Forces, Tianjin, 300162, People's Republic of China.
³ College of Pharmacy, The State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, People's Republic of China. Electronic address: Guang.yang@nankai.edu.cn.
⁴ College of Pharmacy, The State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, People's Republic of China. Electronic address: honggang.zhou@vip.126.com.
⁵ College of Pharmacy, The State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, People's Republic of China. Electronic address: Cheng.yang@nankai.edu.cn.

PMID: 30096654
DOI: 10.1016/j.ejmech.2018.07.074

Abstract

In this study, anti-IPF lead compounds 42 and 44, derived from natural sesquiterpene lactones Isoalantolactone and alantolactone, were discovered by screening from a high-throughput TGF-β1 reporter luciferase assay. Notably, they could reduce the myofibroblast activation and extracellular matrix deposition both in vitro and in vivo. Additionally, compounds 42 and 44 could significantly attenuate bleomycin-induced pulmonary fibrosis in mice. Further validation of pharmacokinetics study and toxicity evaluation indicated that compound 44 might be a promising anti-IPF drug candidate.

Keywords: High-throughput screening; Idiopathic pulmonary fibrosis; Isoalantolactone; Sesquiterpene lactone; TGF-β1/p-smad3 signaling pathway.

MeSH terms

Animals
Bleomycin
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Fibroblasts / drug effects
High-Throughput Screening Assays
Idiopathic Pulmonary Fibrosis / chemically induced
Idiopathic Pulmonary Fibrosis / drug therapy*
Idiopathic Pulmonary Fibrosis / metabolism
Lactones / chemical synthesis
Lactones / chemistry
Lactones / pharmacology*
Mice
Molecular Structure
NIH 3T3 Cells
Sesquiterpenes / chemical synthesis
Sesquiterpenes / chemistry
Sesquiterpenes / pharmacology*
Sesquiterpenes, Eudesmane / chemical synthesis
Sesquiterpenes, Eudesmane / chemistry
Sesquiterpenes, Eudesmane / pharmacology*
Structure-Activity Relationship
Transforming Growth Factor beta1 / antagonists & inhibitors*
Transforming Growth Factor beta1 / metabolism

Substances

Lactones
Sesquiterpenes
Sesquiterpenes, Eudesmane
Transforming Growth Factor beta1
Bleomycin
alantolactone